The present invention relates to therapies for treatment of cancer, specifically to the synergistic use of two or more anti-cancer agents having antiproliferative cytotoxic and cytostatic activities.
Chemotherapy, the systemic administration of antineoplastic agents that travel throughout the body via the blood circulatory system, along with and often in conjunction with surgery and/or radiation treatment, has for years been widely utilized in the treatment of a wide variety of cancers. Unfortunately, the available chemotherapeutic drugs often fail patients because they kill many healthy cells and thus bring on serious side effects that limit the doses physicians can administer.
In particular, cancerous tumors are difficult to treat because they contain both proliferating and non-proliferating cancer cells. As a cancerous tumor grows, the vascular development often cannot keep pace with the rapid proliferation of malignant cell population. Consequently, solid cancerous tumor masses typically exhibit abnormal blood vessel networks which, unlike vessels in normal tissues, fail to provide adequate nutritional support to the cancerous tumor cells for optimal growth. In most cancerous, solid tumors, non-proliferating tumor cells constitute the majority of the total tumor cell population. Moreover, as a tumor grows in size the proportion of non-proliferating tumor cells also increases in proportion. As most current anti-cancer agents target proliferating cells, the non-proliferating tumor cell population has been implicated as a major contributing factor in the failure of radiation or chemotherapy used alone or together to cure neoplastic disease.
As mentioned above, as a tumor grows in size, it typically becomes more refractory to most chemotherapies. Accordingly, many tumor eradication procedures include a debulking step to decrease the mass of the tumor prior to the administration of anti-neoplastic agents. However, debulking does not always result in tumor eradication, even when combined with powerful chemotherapeutic agents. Accordingly, there is a need in the art for new treatments that target both proliferating and non-proliferating cancer cells for the treatment of malignancy.
WO 98/54966 discloses combination therapies employing an antineoplastic agent or radiation therapy in conjunction with an inhibitor of prenyl-protein transferase which may be useful in the treatment of cancer. However, WO 98/54966 does not disclose the use of the formula I compounds of the present invention.
U.S. Pat. No. 6,011,029 discloses the formula I compounds of the present invention and provides methods for their use as anti-cancer agents. In addition, that patent generically discloses that the formula I compounds may be useful in combination with other cancer therapies. However, U.S. Pat. No. 6,011,029 does not disclose any specific combination treatments nor does it disclose or suggest combination treatments which act synergistically as anti-cancer treatments.
It is, therefore, an object of the present invention to provide a synergistic method for the treatment of cancer.
It is also an object of the present invention to provide a pharmaceutical composition for the synergistic treatment of cancer.
Those and other objects of the present invention will become more apparent from the description thereof set forth below.
The present invention provides a synergistic method for the treatment of cancer which comprises administering to a mammalian specie in need thereof a synergistically, therapeutically effective amount of: (1) at least one agent selected from the group consisting of anti-proliferative cytotoxic agents and anti-proliferative cytostatic agents, and (2) a compound of formula I 
or a pharmaceutically acceptable salt thereof wherein
R1 is Cl, Br, CN, optionally substituted phenyl, or optionally substituted 2-,3- or 4-pyridyl;
R2 is optionally substituted lower alkyl, or optionally substituted aralkyl;
R3 and R5 are each independently optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heterocyclo;
R4 is hydrogen or lower alkyl;
Z1 is CO, SO2, CO2 or SO2N(R5)xe2x80x94; and
n is 1 or 2;
provided that the cytotoxic agent and/or cytostatic agent is administered simultaneous with or prior to the formula I compound.
The present invention further provides a pharmaceutical composition for the synergistic treatment of cancer which comprises at least one agent selected from the group consisting of anti-proliferative cytotoxic agents and anti-proliferative cytostatic agents, and a compound of formula I, and a pharmaceutically acceptable carrier.
In a preferred embodiment of the invention the cytotoxic or cytostatic agent is administered prior to the administration of a compound of formula I. In another embodiment of the invention, the cytotoxic or cytostatic agent is administered simultaneously with the compound of formula I.